Requirement of c-Myb for p210BCR/ABL-dependent transformation of hematopoietic progenitors and leukemogenesis

Department of Cancer Biology, and Kimmel Cancer Center, Thomas Jefferson University Medical College, Philadelphia, PA 19107, USA.
Blood (Impact Factor: 10.43). 06/2008; 111(9):4771-9. DOI: 10.1182/blood-2007-08-105072
Source: PubMed

ABSTRACT The c-Myb gene encodes a transcription factor required for proliferation and survival of normal myeloid progenitors and leukemic blast cells. Targeting of c-Myb by antisense oligodeoxynucleotides has suggested that myeloid leukemia blasts (including chronic myelogenous leukemia [CML]-blast crisis cells) rely on c-Myb expression more than normal progenitors, but a genetic approach to assess the requirement of c-Myb by p210(BCR/ABL)-transformed hematopoietic progenitors has not been taken. We show here that loss of a c-Myb allele had modest effects (20%-28% decrease) on colony formation of nontransduced progenitors, while the effect on p210(BCR/ABL)-expressing Lin(-) Sca-1(+) and Lin(-) Sca-1(+)Kit(+) cells was more pronounced (50%-80% decrease). Using a model of CML-blast crisis, mice (n = 14) injected with p210(BCR/ABL)-transduced p53(-/-)c-Myb(w/w) marrow cells developed leukemia rapidly and had a median survival of 26 days, while only 67% of mice (n = 12) injected with p210(BCR/ABL)-transduced p53(-/-)c-Myb(w/d) marrow cells died of leukemia with a median survival of 96 days. p210(BCR/ABL)-transduced c-Myb(w/w) and c-Myb(w/d) marrow progenitors expressed similar levels of the c-Myb-regulated genes c-Myc and cyclin B1, while those of Bcl-2 were reduced. However, ectopic Bcl-2 expression did not enhance colony formation of p210(BCR/ABL)-transduced c-Myb(w/d) Lin(-)Sca-1(+)Kit(+) cells. Together, these studies support the requirement of c-Myb for p210(BCR/ABL)-dependent leukemogenesis.

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    • "Interestingly, two of them (Sp1 and CEBPa) are mainly involved in the regulation of gene expression but, more importantly, the other two (c-myb and MZF-1) are typically linked to the hematopoietic system. In fact, c-myb is required for regulating the proliferation and survival of normal myeloid progenitors and leukemic blast cells, while MZF-1 is usually associated with the differentiation of the hematopoietic stem cells (Lidonnici et al., 2008; Morris et al., 1995). Our chromatin immunoprecipitation experiments showed that the four selected transcription factors were only partially recruited to PLC-b1 promoter before the start of epigenetic therapy. "
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    • "In particular, MDS patients responding to azacitidine therapy were reported to show a specific recruitment to PI- PLCb1 promoter of myeloid zinc finger (MZF)-1, but not c-myb. This is particularly appealing, since MZF-1 plays a role in myeloid differentiation (Morris et al., 1995), whereas c-myb is specifically associated with hematopoietic stem cell proliferation (Lidonnici et al., 2008), therefore confirming the involvement of PI-PLCb1 in azacitidine-induced myeloid differentiation (Fig. 1). "
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